Katrina M Miranda
Work Summary
We seek to produce new drugs that harness molecules produced during the natural immune response in order to treat cancer and pain. Such compounds may also provide new treatments for heart failure and alcoholism.
We seek to produce new drugs that harness molecules produced during the natural immune response in order to treat cancer and pain. Such compounds may also provide new treatments for heart failure and alcoholism.
PMID: 19577638;Abstract:
Nitroxyl (HNO), the one-electron reduced and protonated congener of nitric oxide (NO), is a chemically unique species with potentially important biological activity. Although HNO-based pharmaceuticals are currently being considered for the treatment of chronic heart failure or stroke/transplant-derived ischemia, the chemical events leading to therapeutic responses are not established. The interaction of HNO with oxidants results in the well-documented conversion to NO, but HNO is expected to be readily reduced as well. Recent thermodynamic calculations predict that reduction of HNO is biologically accessible. Herein, kinetic analysis suggests that the reactions of HNO with several mechanistically distinct reductants are also biologically feasible. Product analysis verified that the reductants had in fact been oxidized and that in several instances HNO had been converted to hydroxylamine. Moreover, a theoretical analysis suggests that in the reaction of HNO with thiol reductants, the pathway producing sulfinamide is significantly more favorable than that leading to disulfide. Additionally, simultaneous production of HNO and NO yielded a biphasic oxidative capacity. © 2009 Elsevier Inc. All rights reserved.
The primary product of the interaction between nitric oxide (NO) and superoxide (O-2(-)) is peroxynitrite (ONOO-), which is capable of either oxidizing or nitrating various biological substrates. However, it has been shown that excess NO or O-2(-) can further react with ONOO- to form species which mediate nitrosation, Subsequently, the controlled equilibrium between nitrosative and oxidative chemistry is critically dependent on the flux of NO and O-2(-). Since ONOO- reacts not only with NO and O-2(-) but also with CO2, the effects of bicarbonate (HCO3-) on the biphasic oxidation profile of dihydrorhodamine-123 (DHR) and on the nitrosation of both 2,3-diaminonaphthalene and reduced glutathione were examined. Nitric oxide and O-2(-) were formed with DEA/NO [NaEt2NN(O)NO] and xanthine oxidase, respectively. The presence of HCO3- did not alter either the oxidation profile of DHR with varying radical concentrations or the affinity of DHR for the oxidative species. This suggests that the presence of CO2 does not affect the scavenging of ONOO- by either NO or O-2(-). However, an increase in the rate of DHR oxidation by ONOO- in the presence of HCO3- suggests that a CO2-ONOO- adduct does play a role in the interaction of NO or O-2(-) with a product derived from ONOO-. Further examination of the chemistry revealed that the intermediate that reacts with NO is neither ONOO- nor cis-HOONO. It was concluded that NO reacts with both trans-HOONO and a CO2 adduct of ONOO- to form nitrosating species which have similar oxidation chemistry and reactivity with O-2(-) and NO. (C) 1999 Academic Press.
Nitrosative stress can occur when reactive nitric oxide (NO) species compromise the function of biomolecules via formation of NO adducts on critical amine and thiol residues. The capacity of inducible nitric-oxide synthase (iNOS) to generate nitrosative stress was investigated in the murine macrophage line ANA-1. Sequential activation with the cytokines IFN-gamma and either tumor necrosis factor-alpha or interleukin-1 beta resulted in the induction of iNOS and production of nitrite (20 nM/min) but failed to elicit nitrosation of extracellular 2,3-diaminonapthalene. Stimulation with IFN-gamma and bacterial lipopolysaccharide increased the relative level of iNOS protein and nitrite production of ANA-1 cells S-fold; however, a substantial level of NO in the media was also observed, and nitrosation of 2,3-diaminonapthalene was increased greater than 30-fold. Selective scavenger compounds suggested that the salient nitrosating mechanism was the NO/O-2 reaction leading to N2O3 formation. These data mimicked the pattern observed with a 5 mu M concentration of the synthetic NO donor (Z)-1-[N-ammoniopropyl) -N-(n-propyl) aminoldiazen-1-ium- 1,2-diolate (PAPA/NO), The NO profiles derived from iNOS can be distinct and depend on the inductive signal cascades. The diverse consequences of NO production in macrophages may reside in the cellular mechanisms that control the ability of iNOS to form N2O3 and elicit nitrosative stress.
PMID: 15822180;Abstract:
Recent discoveries of novel and potentially important biological activity have spurred interest in the chemistry and biochemistry of nitroxyl (HNO). It has become clear that, among all the nitrogen oxides, HNO is unique in its chemistry and biology. Currently, the intimate chemical details of the biological actions of HNO are not well understood. Moreover, many of the previously accepted chemical properties of HNO have been recently revised, thus requiring reevaluation of possible mechanisms of biological action. Herein, we review these developments in HNO chemistry and biology.